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Role of calcitonin gene-related peptide and brain natriuretic peptide to modulate the excitability state of trigeminal neurons: relevance to migraine pathology and treatment

Authors Vilotti S, Fabbretti E, Nistri A

Received 27 October 2014

Accepted for publication 28 November 2014

Published 19 January 2015 Volume 2015:8 Pages 31—41


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Professor Trevor W. Stone

Sandra Vilotti,1 Elsa Fabbretti,2 Andrea Nistri1

1Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy; 2Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, Slovenia

Abstract: Hyperactivity of trigeminal sensory neurons is a major process to generate recurrent headache, typical of migraine attacks. How physiological nociception is converted into strong pathological pain remains, however, poorly understood. In recent years, certain neuropeptides and their receptors have been shown to modulate sensory neuron nociception and to contribute to the persistent hyperalgesia due to the sensory stimulus sensitization that defines the clinical experience of chronic pain syndromes, including migraine. Using calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP) as examples, this review addresses the mechanisms through which neuropeptides might modulate nociceptor activity. One attractive notion is that pain signaling by trigeminal sensory neurons is potently regulated by the ambient levels of these peptides: CGRP is thought to facilitate neuronal firing responsible for trigeminal sensitization necessary to trigger headache, whereas BNP is proposed to act as a negative regulator of trigeminal neuron activity. For either peptide, the key target appears to be the ATP-gated P2X3 receptor that, widely expressed by trigeminal sensory neurons, generates fast, large excitation to release glutamate onto second-order brain neurons. The fine balance between the activities of these peptides is suggested to ultimately determine whether nociception is perceived at higher center as a physiological or pathological response. Hence, the clinical goal of CGRP antagonism using either pharmacological receptor blockers or monoclonal antibodies (to sequester this peptide or to directly inhibit its receptor) is currently considered a novel approach for migraine prophylaxis and to treat acute headache attacks.

Keywords: trigeminal ganglion, headache, sensory neurons, P2X3, TRPV1

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